Development of Emergent PET Tracers in Frontotemporal Lobar Degeneration

额颞叶变性紧急 PET 示踪剂的开发

• 批准号: 10429831
• 负责人: David Nima Soleimani-Meigooni
• 金额: $ 19.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429831
• 关键词: Advanced Development; Affinity; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Area; Argyrophilic Grain Disease; Autopsy; Basal Ganglia; Behavioral; Binding; Biological Markers; Biometry; Brain; Brain Diseases; C9ORF72; California; Categories; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognitive; Data; Data Collection; Dementia; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease Progression; Drug Kinetics; Environment; Evaluation; Fluorine; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Genetic; Globus Pallidus; Goals; Grant; Hippocampus (Brain); Immunoassay; Immunohistochemistry; In Vitro; Individual; Infrastructure; Integral Membrane Protein; K-Series Research Career Programs; Label; Lead; Learning; Ligand Binding; Ligands; Magnetic Resonance Imaging; Measures; Medial; Memory; Mentors; Mentorship; Methods; Modeling; Monitor; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Operations Research; Orphan Drugs; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patient Recruitments; Patients; Pattern; Phenotype; Pick Disease of the Brain; Positron-Emission Tomography; Presynaptic Terminals; Primary Progressive Aphasia; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; Recombinants; Research; Research Design; Research Ethics; Research Personnel; Resources; San Francisco; Scientist; Semantics; Sensitivity and Specificity; Site; Standardization; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Synaptic Vesicles; Synaptophysin; Syndrome; Tauopathies; Technical Expertise; Techniques; Temporal Lobe; Thick; Tracer; Training; Translations; Universities; Validation; Variant; analog; brain magnetic resonance imaging; career; career development; clinical diagnosis; clinical diagnostics; corticobasal degeneration; corticobasal syndrome; diagnostic criteria; disorder control; drug development; early onset; experience; hyperphosphorylated tau; improved; in vivo; in vivo imaging; instructor; meetings; mild cognitive impairment; molecular pathology; mutation carrier; neuroimaging; neuroimaging marker; neuropathology; novel; pharmacokinetic model; precision medicine; preclinical development; programs; protein TDP-43; putamen; radiotracer; recruit; research and development; research clinical testing; skills; tau Proteins; tau aggregation; treatment response; uptake

PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. David Soleimani-Meigooni, a behavioral neurologist and Clinical Instructor who is establishing himself as a junior investigator at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). His long-term goal is to become a clinician-scientist who will lead an independent research program to advance the pre-clinical development/translation of novel PET tracers for diagnosis and monitoring of neurodegenerative diseases associated with frontotemporal lobar degeneration (FTLD) pathology. Through the K23 and the optimal training environment and resources of the MAC, Dr. Soleimani-Meigooni aims to achieve these training goals: 1. To become proficient in pharmacokinetic radiotracer modeling and optimization of PET image acquisition. 2. To become proficient in quantitative PET analyses. 3. To learn quantitative neuropathology techniques. 4. To gain advanced skills in study design and biostatistics. 5. To gain skills in clinical research operations, research ethics, and grantsmanship. 6. To implement his K23 training and findings into an R01 that will allow him to become an independent investigator involved in pre-clinical development/translation of novel PET tracers for FTLD. To achieve these training goals, Dr. Soleimani-Meigooni has assembled a world-class mentorship team including primary mentor, Dr. Gil Rabinovici, a behavioral neurologist and leader in PET neuroimaging of neurodegenerative diseases; co-mentor, Dr. William Jagust, a behavioral neurologist and expert in technical aspects of PET imaging, including radiotracer development and pharmacokinetic modeling; co-mentor, Dr. Lea Grinberg, a neuropathologist, co-leader of the UCSF Neurodegenerative Disease Brain Bank, and expert on FTLD and quantitative neuropathological measures; collaborator, Dr. Suzanne Baker, a scientist with technical expertise in PET imaging; and, collaborator, Dr. Isabel Elaine Allen, an expert biostatistician. This project will evaluate/validate new PET tracers to aid in diagnosis and monitoring of FTLD. Candidate PET tracers include a novel ligand that binds to non-Alzheimer tau proteins, [18F]PI-2620, and another ligand that binds to synapses, [18F]SynVesT-1. Further evaluation is needed to determine if [18F]PI-2620 can distinguish FTLD with tau pathology (FTLD-tau) from FTLD with TDP-43 pathology (FTLD-TDP), and if [18F]SynVesT-1 is a sensitive marker of synapse loss and disease state in FTLD. In this project, both tracers will be evaluated/validated by comparing patterns of tracer retention in patients with FTLD-tau to FTLD-TDP and other neurodegenerative diseases (Aim 1); correlating regional tracer retention to clinical measures and structural brain MRI changes (loss of cortical thickness or subcortical volume) (Aim 2); and performing quantitative PET-to-pathology correlations (Aim 3). This project provides critical data that could support the translation of these radiotracers for clinical use and application as clinical trial biomarkers.

项目摘要/摘要 这是一份K23职业发展奖的申请，申请人是行为科学家大卫·索莱曼尼-梅古尼博士。 神经学家和临床导师谁是建立自己作为一个初级研究员在大学 加州，旧金山弗朗西斯科（UCSF）记忆和衰老中心（MAC）。他的长期目标是成为 临床科学家，将领导一个独立的研究项目，以推进临床前 用于诊断和监测神经变性疾病的新型PET示踪剂的开发/翻译 与额颞叶变性（FTLD）病理学相关。通过K23和最佳训练 环境和资源的MAC，Soleimani-Meigooni博士旨在实现这些培训目标：1。到 精通药物代谢动力学放射性示踪剂建模和PET图像采集优化。2.到 精通PET定量分析。3.学习定量神经病理学技术。4.获得 研究设计和生物统计学方面的高级技能。5.获得临床研究操作技能，研究 道德和伦理6.将他的K23培训和发现落实到R 01中，使他能够 成为一名独立的研究者，参与新型PET示踪剂的临床前开发/翻译， FTLD。为了实现这些培训目标，Soleimani-Meigooni博士组建了一个世界级的导师团队 包括主要导师，Gil Rabinovici博士，一位行为神经学家和PET神经成像的领导者， 神经退行性疾病;共同导师，William Jagust博士，行为神经学家和技术专家 PET成像方面，包括放射性示踪剂开发和药代动力学建模;共同导师，莱亚博士 格林伯格是一位神经病理学家，加州大学旧金山分校神经退行性疾病脑库的共同负责人，也是神经病理学专家。 FTLD和定量神经病理学测量;合作者，Suzanne Baker博士，一位技术科学家 PET成像专业知识;以及合作者，生物统计学专家伊莎贝尔伊莱恩艾伦博士。 该项目将评估/验证新的PET示踪剂，以帮助诊断和监测FTLD。候选 PET示踪剂包括与非阿尔茨海默病tau蛋白结合的新型配体，[18 F]PI-2620和另一种配体 与突触结合的[18F]SynVesT-1。需要进一步评价以确定[18F]PI-2620是否可以 区分具有tau病理的FTLD（FTLD-tau）与具有TDP-43病理的FTLD（FTLD-TDP），并且如果 [18F]SynVesT-1是FTLD中突触丢失和疾病状态的敏感标志物。在这个项目中， 将通过比较FTLD-tau患者与FTLD-TDP患者的示踪剂保留模式进行评价/验证 和其他神经退行性疾病（目标1）;将区域示踪剂保留与临床测量相关联， 结构性脑MRI变化（皮质厚度或皮质下体积的损失）（目标2）;以及 定量PET与病理学相关性（目标3）。该项目提供了关键数据，可以支持 将这些放射性示踪剂转化为临床使用和作为临床试验生物标志物的应用。